Estimation of passive gastrointestinal absorption of new dual DNA gyrase and topoisomerase IV inhibitors using PAMPA and biopartitioning micellar chromatography and quantitative structure-retention relationship analysis
Vladimir Dobričić , Marko Marodi , Bojan Marković , Tihomir Tomašič , Martina Durcik , Nace Zidar , Lucija Peterlin Mašič , Janez Ilaš , Danijel Kikelj , Olivera Čudina
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引用次数: 0
Abstract
DNA gyrase and topoisomerase IV play significant role in maintaining the correct structure of DNA during replication and they have been identified as validated targets in antibacterial drug discovery. Inadequate pharmacokinetic properties are responsible for many failures during drug discovery and their estimation in the early phase of this process maximizes the chance of getting useful drug candidates. Passive gastrointestinal absorption of a selected group of thirteen dual DNA gyrase and topoisomerase IV inhibitors was estimated using two in vitro tests – parallel artificial membrane permeability assay (PAMPA) and biopartitioning micellar chromatography (BMC). Due to good correlation between obtained results, passive gastrointestinal absorption of remaining ten compounds was estimated using only BMC. With this experimental setup, it was possible to identify compounds with high values of retention factors (k) and highest expected passive gastrointestinal absorption, and compounds with low values of k for which low passive gastrointestinal absorption is predicted. Quantitative structure-retention relationship (QSRR) modelling was performed by creating multiple linear regression (MLR), partial least squares (PLS) and support vector machines (SVM) models. Descriptors with the highest influence on retention factor were identified and their interpretation can be used for the design of new compounds with improved passive gastrointestinal absorption.
利用 PAMPA 和生物分馏胶束色谱法以及定量结构-保留关系分析估算新型 DNA 回旋酶和拓扑异构酶 IV 双抑制剂的被动胃肠道吸收率
DNA 回旋酶和拓扑异构酶 IV 在复制过程中维持 DNA 的正确结构方面发挥着重要作用,它们已被确定为抗菌药物研发的有效靶点。药代动力学特性不足是药物发现过程中许多失败的原因,而在这一过程的早期阶段对它们进行估计,可以最大限度地提高获得有用候选药物的机会。通过平行人工膜渗透性试验(PAMPA)和生物颗粒胶束色谱法(BMC)这两种体外试验,对选定的 13 种 DNA 回旋酶和拓扑异构酶 IV 双抑制剂的被动胃肠道吸收进行了估计。由于获得的结果之间具有良好的相关性,因此仅使用 BMC 对其余十种化合物的被动胃肠道吸收进行了估计。通过这种实验设置,可以确定哪些化合物的保留因子(k)值高,被动胃肠道吸收率最高;哪些化合物的保留因子(k)值低,被动胃肠道吸收率较低。通过建立多元线性回归(MLR)、偏最小二乘法(PLS)和支持向量机(SVM)模型,进行了定量结构-保留关系(QSRR)建模。研究发现了对保留因子影响最大的描述因子,其解释可用于设计可改善被动胃肠道吸收的新化合物。
期刊介绍:
The Journal of Chromatography B publishes papers on developments in separation science relevant to biology and biomedical research including both fundamental advances and applications. Analytical techniques which may be considered include the various facets of chromatography, electrophoresis and related methods, affinity and immunoaffinity-based methodologies, hyphenated and other multi-dimensional techniques, and microanalytical approaches. The journal also considers articles reporting developments in sample preparation, detection techniques including mass spectrometry, and data handling and analysis.
Developments related to preparative separations for the isolation and purification of components of biological systems may be published, including chromatographic and electrophoretic methods, affinity separations, field flow fractionation and other preparative approaches.
Applications to the analysis of biological systems and samples will be considered when the analytical science contains a significant element of novelty, e.g. a new approach to the separation of a compound, novel combination of analytical techniques, or significantly improved analytical performance.